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Cardiomyopathy Associated with the Ala143thr Variant of the Α

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Cardiomyopathy Associated with the Ala143thr Variant of the Α Heart failure and cardiomyopathies ORIGINAL RESEARCH Heart: first published as 10.1136/heartjnl-2019-315933 on 16 January 2020. Downloaded from Cardiomyopathy associated with the Ala143Thr variant of the α-galactosidase A gene Kati Valtola,1 Juanita Nino- Quintero,2 Marja Hedman,2 Line Lottonen-­Raikaslehto,2 Tomi Laitinen,2 Maleeha Maria,3 Ilkka Kantola,4,5 Anita Naukkarinen,2 Markku Laakso,3 Johanna Kuusisto 6,7 ► Additional material is ABSTRact the late- onset form of FD, which is more common published online only. To view, Objective To investigate whether the Ala143Thr than the classic type, patients have residual enzyme please visit the journal online activity. Cardiomyopathy is often the predominant (http:// dx. doi. org/ 10. 1136/ variant of the α-galactosidase A gene (A143T/GLA), with heartjnl- 2019- 315933). conflicting interpretations of pathogenicity, is associated or the only manifestation of the late- onset disease, with Fabry cardiomyopathy. and typically develops in the middle age in hemi- 1 1 Heart Center, Kuopio University Methods The index patient, a woman in her 60s zygous and heterozygous subjects. Cardiovascular Hospital, Kuopio, Finland 2 2 with cardiomyopathy, was screened for variants in complications are the major cause of death in FD. Diagnostic Imaging Center, Kuopio University Hospital, 59 cardiomyopathy- related genes. A143T/GLA, the Enzyme replacement therapy (ERT) is an effective Kuopio, Finland only rare variant found, was screened in 10 relatives. treatment for FD when started before permanent 3Genome Center of Eastern GLA activity and lyso-­Gb3 levels were measured and organ damage develops.3 Finland, University of Eastern echocardiography was performed in 8 of 9 subjects Genetic analyses are currently widely used in the Finland School of Medicine, carrying A143T/GLA. Cardiac magnetic resonance (CMR) diagnosis of cardiomyopathies.4 In a large cohort of Kuopio, Finland 18 4Division of Medicine, Turku imaging and F- fluorodeoxyglucose (FDG) positron European patients with hypertrophic cardiomyop- University Hospital, Turku, emission tomography/CT (PET/CT) were performed in athy, GLA mutations accounted for 0.5% of cases.5 Finland In other studies, 3%–6.3% of males with hypertro- 5 four adult A143T/GLA carriers. Endomyocardial biopsy School of Medicine, University phic cardiomyopathy were diagnosed with FD.6 of Turku, Turku, Finland was obtained from two adult A143T/GLA carrying sons 6Department of Medicine, of the index patient. The pathogenicity and clinical importance of all Kuopio University Hospital, Results The index patient and her elder son had GLA variants, however, is not clear. Particularly, the Kuopio, Finland missense variant Ala143Thr of GLA (c.427G>A; 7 a pacemaker implantation because of sick sinus Centre for Medicine and syndrome and atrioventricular block. GLA activities were A143T/GLA), common in the newborn screening Clinical Research, University in some areas of the USA and patient populations of Eastern Finland School of decreased to 25%–40% of normal in both sons and Medicine, Kuopio, Finland one granddaughter. Lyso-­Gb3 levels were elevated in with FD, has been considered pathogenic in several both sons. In CMR, the index patient and her two sons studies but benign in others.7–18 http://heart.bmj.com/ Correspondence to had left ventricular (LV) hypertrophy and/or dilatation. In the present study, we describe a Finnish family Professor Johanna Kuusisto, The elder son had late gadolinium enhancement, high with A143T/GLA and cardiomyopathy. Our aim Department of Medicine, Kuopio CMR- derived T1 time and positive FDG signal in PET/CT was to investigate the association of A143T/GLA University Hospital, Kuopio with cardiomyopathy in the family, and to examine 70210, Finland; in the basal inferolateral LV wall. The younger son had johanna. kuusisto@ kuh. fi low T1 time and the mother had positive FDG signal in by clinical, biomarker, cardiac imaging and histolog- PET/CT in the basal inferolateral LV wall. Endomyocardial ical methods if cardiomyopathy in family members Received 12 September 2019 biopsy of both sons showed myocardial accumulation is compatible with Fabry cardiomyopathy. Revised 13 November 2019 on October 1, 2021 by guest. Protected copyright. Accepted 18 November 2019 compatible with glycolipids in light and electron microscopy, staining with anti-­Gb3 antibody available for METHODS the younger son. Five female relatives with A143T/GLA had no cardiomyopathy in cardiac imaging. Study design Conclusions A143T/GLA is likely a late- onset Fabry The present family study started with two members cardiomyopathy causing variant with incomplete of a Finnish family from the Kuopio University Hospital area, who had cardiomyopathy, and ► http:// dx. doi. org/ 10. 1136/ penetrance. heartjnl- 2019- 316143 included investigation of altogether 11 family members (figure 1). © Author(s) (or their INTRODUCTION Genetic analysis of 59 cardiomyopathy-related employer(s)) 2020. Re- use Fabry disease (FD) is a rare X- chromosome linked genes permitted under CC BY-­NC. No lysosomal storage disorder caused by mutations Genetic analysis was performed in the Genome commercial re- use. See rights and permissions. Published in the α-galactosidase A gene (GLA). According Center of the University of Eastern Finland. The by BMJ. to Human Gene Mutation Database, over 900 genetic screening from the DNA of the index mutations GLA have been reported worldwide. patient and his two sons with cardiomyopathy To cite: Valtola K, Nino- GLA mutations result in functionally deficient covered coding regions of the 59 genes related to Quintero J, Hedman M, et al. Heart Epub ahead of GLA enzyme, which leads to progressive accumu- cardiomyopathy, including GLA. Cascade screening print: [please include Day lation of glycosphingolipid substrates, particularly of A143T/GLA was performed with Sanger Month Year]. doi:10.1136/ globotriaosylceramide (Gb3) and globotriaosyl- sequencing in all available relatives (n=10). For heartjnl-2019-315933 sphingosine (lyso-Gb3) in different organs.1 In details see online supplementary information. Valtola K, et al. Heart 2020;0:1–7. doi:10.1136/heartjnl-2019-315933 1 Heart failure and cardiomyopathies included cine imaging, late gadolinium enhancement (LGE) images and image analysis. Non-contrast myocardial T1 mapping Heart: first published as 10.1136/heartjnl-2019-315933 on 16 January 2020. Downloaded from was available in both sons of the index patient. For details see online supplementary information. 18F-fluorodeoxyglucose positron emission tomography/CT All available adult A143T/GLA carriers (n=4) underwent 18F- flu- orodeoxyglucose (FDG) positron emission tomography/CT (PET/CT). PET/CT was used to characterise cardiac metabolic activity and to monitor treatment response in cardiac glucose uptake. Maximum standardised uptake value (SUV) was deter- mined. To calculate the metabolic volumes of abnormal FDG uptake, a threshold of SUV 2.7 was used. PET scanning results were analysed by clinical physiologists (JN- Q, TL). For details see online supplementary information. Figure 1 The family tree of the index patient (arrow) carrying Ala143Thr variant of the α-galactosidase A gene (A143T/GLA). Of 11 Endomyocardial biopsy family members tested, 8 were carriers of A143T/GLA. Both A143T/GLA- Endomyocardial biopsy was performed in two A143T/GLA- positive males and a young female had decreased levels of GLA activity positive sons of the index patient, who had signs of cardio- in leucocytes. Cardiomyopathy was diagnosed in the female index myopathy. Myocardial specimens for histological analysis, patient in her 60s, her son in his 30s and her son in his 20s. immunohistochemistry and electron microscopy were obtained. Several representative biopsies were taken. Myocardial specimens were stained for light and transmission electron microscopy in In silico structural analysis of mutated GLA protein both sons. Immunohistochemical staining with an anti-Gb3 anti- Molecular structure of A143T/GLA mutated protein was body was available in the younger son. Specimen were analysed obtained using in silico structural analysis. For details see online in the Diagnostic Imaging Center of Kuopio University Hospital supplementary information. by a senior cell biologist (AN). For details see online supplemen- tary information. GLA enzyme activity and lyso-Gb3 levels GLA enzyme activity and lyso- Gb3 levels were measured in RESUltS available A143T/GLA- positive subjects (n=7). For details see Genetic findings online supplementary information. In the genetic screening of the index patient in her 60s, her son in his 30s and the son in his 20s with cardiomyopathy, A143T/GLA Clinical examination was found. No other pathogenic or likely pathogenic variants were identified in 59 cardiomyopathy- related genes. In the Family members with A143T/GLA living in Finland (n=7) were http://heart.bmj.com/ examined at the Heart Center of the Kuopio University Hospital cascade genetic screening, five additional relatives, all females (n=6) or at the Heart Hospital of the Tampere University aged from 7 to 69 years, carried A143T/GLA (figure 1). Hospital (n=1) according to Finnish FD protocol.19 A paediatri- cian examined the children (n=2), and a cardiologist (KV) and Molecular structure of A143T mutated GLA protein an internist examined the adults (n=5). The standard 12- lead The residue is located on the surface of the GLA protein. The ECG was recorded in all adult subjects. Examinations by an mutant residue (threonine)
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